Process for the preparation of (1r,2r)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol

ABSTRACT

The present invention relates to a process for the preparation of (1R,2R)-3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol.

The present invention relates to a process for the preparation of(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol.

A class of active ingredients having excellent analgesic effectivenessand very good tolerability are the substituteddimethyl-(3-aryl-butyl)-amine compounds, which are known inter alia fromEP 0 693 475. In particular,(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol has proven tobe a very promising candidate for the development of an analgesic inclinical trials.

An object of the present invention was, therefore, to provide a processwhich allows for the preparation of(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol via a shortroute with good overall yield under environmentally acceptableconditions.

In particular, in the process of the present invention all stereocenterscan be established via substrate control with almost exclusive formationof only a single diastereomer thus sparing elaborate purification stepsto separate stereoisomers and costly chiral reagents, catalysts orligands. As there are not any undesired side products formed in theprocess of the present invention, each batch can work at its optimalcapacity.

The object of the present invention is met by providing a process forpreparing (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, oran acid addition salt thereof, comprising the step of (a) reacting acompound of general formula (I),

wherein R represents —C₁₋₆-alkyl, —C₃₋₈-cycloalkyl,—C₁₋₃-alkylene-phenyl, —C₁₋₃-alkylene-naphthyl, tetrahydropyranyl or—C(═O)—C₁₋₆-alkyl, with ethyl magnesium halide in an inert reactionmedium under Grignard conditions.

Preferably R represents methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl,—C(═O)—CH₃, —C(═O)—C₂H₅, —C(═O)—CH(CH₃)₂ or —C(═O)—C(CH₃)₃ in thecompounds of general formula (I). Particularly preferably R representsmethyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl,phenethyl, tetrahydropyranyl or —C(═O)—CH₃ in the compounds of generalformula (I). More particularly preferably R represents methyl, benzyl ortetrahydropyranyl in the compounds of general formula (I).

Yet more preferably R in general formula (I) represents methyl. Thus,very preferably(S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one isreacted with ethyl magnesium halide in an inert reaction medium underGrignard conditions.

Preferably ethyl magnesium bromide or ethyl magnesium chloride are usedas ethyl magnesium halide in step a).

The reaction according to step (a) is preferably carried out in an inertreaction medium, preferably in an organic ether, for example, selectedfrom the group consisting of diethyl ether, tetrahydrofuran,2-methyltetrahydrofuran, tert-butylmethyl ether or any mixture thereof.The reaction is particularly preferably carried out in tetrahydrofuranwith ethyl magnesium chloride at a concentration from 0.5 M to 2 M ofthe ethyl magnesium chloride. Particularly preferably the reaction iscarried out at a concentration of 1 M or 2 M of the ethyl magnesiumchloride.

Another object of the present invention is a process for preparing(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acidaddition salt thereof, comprising the step of (a) reacting a compound ofgeneral formula (I),

wherein R represents —C₁₋₆-alkyl, —C₃₋₈-cycloalkyl,—C₁₋₃-alkylene-phenyl, —C₁₋₃-alkylene-naphthyl, tetrahydropyranyl or—C(═O)—C₁₋₆-alkyl, with ethyl magnesium halide in an inert reactionmedium under Grignard conditions,(b) transferring the thus obtained compound of general formula (II),

wherein R has the above defined meaning, to a compound of generalformula (III),

wherein R has the above defined meaning, optionally in form of an acidaddition salt,(c) deprotecting the thus obtained compound of general formula (III) toobtain (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol offormula (IV),

(d) optionally converting the thus obtained(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol into an acidaddition salt.

Preferably R represents methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl,—C(═O)—CH₃, —C(═O)—C₂H₅, —C(═O)—CH(CH₃)₂ or —C(═O)—C(CH₃)₃ in thecompounds of general formulae (I), (II) and (III). Particularlypreferably R represents methyl, ethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or—C(═O)—CH₃ in the compounds of general formulae (I), (II) and (III).More particularly preferably R represents methyl, benzyl ortetrahydropyranyl in the compounds of general formulae (I), (II) and(III).

Even more particularly preferably R represents methyl in the generalformulae (I), (II) and (III). Thus,(S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (Ia) istransformed to(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol by thefollowing sequence of steps (scheme 1).

In case R represents methyl in the general formula (III), compound(IIIa) is preferably reacted with hydrobromic acid or methanesulfonicacid and methionine or diisobutylaluminium hydride in a reaction medium,preferably in a reaction medium selected from the group consisting ofdiethylether, tetrahydrofuran, toluene, 2-methyltetrahydrofuran,dioxane, tert-butyl-methylether and mixtures thereof to yield(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula(IV).

In case R represents C₁₋₆-alkyl except methyl in the general formula(III), the respective compound of general formula (III) is preferablyreacted with hydrobromic acid or diisobutylaluminium hydride in areaction medium, preferably in a reaction medium selected from the groupconsisting of diethylether, tetrahydrofuran, toluene,2-methyltetrahydrofuran, dioxane, tert-butyl-methylether and mixturesthereof to yield(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula(IV).

In case R represents tetrahydropyranyl in the general formula (III), therespective compound of general formula (III) is preferably reacted withat least one inorganic acid, preferably with at least one inorganic acidselected from the group consisting of hydrochloric acid, hydrobromicacid, sulfuric acid and phosphoric acid, optionally in the presence ofat least one salt, preferably at least one salt selected from the groupconsisting of ammonium chloride and potassium hydrogensulfate, in areaction medium, preferably in a reaction medium selected from the groupconsisting of diethylether, tetrahydrofuran, toluene,2-methyltetrahydrofuran, dioxane, tert-butyl-methylether, water andmixtures thereof to yield(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula(IV).

In case R represents —C-₃₋₈-cycloalkyl in the general formula (III), therespective compound of general formula (III) is preferably reacted withhydrobromic acid or diisobutylaluminium hydride in a reaction medium,preferably in a reaction medium selected from the group consisting ofdiethylether, tetrahydrofuran, toluene, 2-methyltetrahydrofuran,dioxane, tert-butyl-methylether and mixtures thereof to yield(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol of formula(IV).

In case R represents —C₁₋₃-alkylene-phenyl or —C₁₋₃-alkylene-naphthyl, acompound of general formula (III) is reacted with hydrobromic acid ordiisobutylaluminium hydride in a reaction medium, preferably in areaction medium selected from the group consisting of diethylether,tetrahydrofuran, toluene, 2-methyltetrahydrofuran, dioxane,tert-butyl-methylether and mixtures thereof or in the presence ofhydrogen and at least one catalyst, preferably in the presence of atleast one catalyst based on palladium or platinum, more preferably inthe presence of palladium on charcoal, in a reaction medium, preferablyin a reaction medium selected from the group consisting of diethylether,tetrahydrofuran, toluene, 2-methyltetrahydrofuran, dioxane,tert-butyl-methylether and mixtures thereof to yield(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula(IV).

In case R represents —C(═O)—C₁₋₆-alkyl in the general formula (III), therespective compound of general formula (III) is preferably reacted withat least one inorganic acid, preferably with at least one inorganic acidselected from the group consisting of hydrochloric acid, hydrobromicacid, sulfuric acid and phosphoric acid, or with at least one inorganicbase, preferably with at least one inorganic base selected from thegroup consisting of sodium hydroxide, potassium hydroxide, sodiumcarbonate and potassium carbonate in a reaction medium, preferably in areaction medium selected from the group consisting of diethylether,tetrahydrofuran, toluene, 2-methyltetrahydrofuran, dioxane,tert-butyl-methylether, water and mixtures thereof to yield(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula(IV).

In another embodiment of the present invention the agent fordeprotecting according to step c) of the inventive process are selectedfrom the group consisting of iodotrimethylsilane, sodium ethyl sulphide,lithium iodide and hydrobromic acid, preferably hydrobromic acid.

The compound (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenolmay be present in form of an acid addition salt, whereby any suitableacid capable of forming such an addition salt may be used.

The conversion of the compound(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol into acorresponding addition salt via reaction with a suitable acid may beeffected in a manner well known to those skilled in the art. Suitableacids include but are not limited to hydrochloric acid, hydrobromicacid, sulphuric acid, methanesulfonic acid, formic acid, acetic acid,oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid,lactic acid, citric acid, glutamic acid and aspartic acid. In apreferred embodiment the acid addition salt is the hydrochloride salt.

The salt formation may preferably be effected in a suitable solventincluding diethyl ether, diisopropyl ether, alkyl acetates, acetone,2-butanone or any mixture thereof. Also preferably, reaction withtrimethylchlorosilane in a suitable solvent may be used for thepreparation of the hydrochloride addition salt.

Preferably a compound of general formula (I) can be obtained by (a′)reacting a compound of general formula (V),

wherein R represents —C₁₋₆-alkyl, —C₁₋₃-alkylene-phenyl,—C₁₋₃-alkylene-naphthyl, tetrahydropyranyl or —C(═O)—C₁₋₆-alkyl, withdimethylamine hydrochloride and paraformaldehyde in an inert reactionmedium under Mannich conditions and(a″) subsequent resolution of the thus obtained compound of generalformula (VI),

wherein R has the above defined meaning.

Preferably R represents methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl,—C(═O)—CH₃, —C(═O)—C₂H₅, —C(═O)—CH(CH₃)₂ or —C(═O)—C(CH₃)₃ in thecompounds of general formulae (V) or (VI). Particularly preferably Rrepresents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or —C(═O)—CH₃ in thecompounds of general formulae (V) or (VI). More particularly preferablyR represents methyl, benzyl or tetrahydropyranyl in the compounds ofgeneral formulae (V) or (VI).

Even more particularly preferably R represents methyl in the generalformulae (V) and (VI). Thus, 1-(3-methoxyphenyl)propan-1-one isconverted to 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one(VIa) with dimethylamine hydrochloride and paraformaldehyde in an inertreaction medium under Mannich conditions.

Preferably the resolution in step (a″) is performed by reacting acompound of general formula (VI) with a chiral acid selected from thegroup consisting of L-(−)-dibenzoyl tartaric acid, L-(−)-dibenzoyltartaric acid.H₂O and D-(−)-tartaric acid, subsequent separation of thethus obtained salt and liberation of the corresponding compound ofgeneral formula (I) in form of the free base.

It is preferred that the resolution is performed in an alcoholicreaction medium selected from the group consisting of methanol, ethanol,1-propanol, 2-propanol and any mixture thereof or in a mixture of analcoholic reaction medium selected from the group consisting ofmethanol, ethanol, 1-propanol, 2-propanol and acetone.

Preferably transfer according to step (b) is performed by (b′)subjecting the compound of general formula (II) to dehydration and (b″)hydrogenation of the thus obtained compound of general formula (VII),

wherein R represents —C₁₋₆-alkyl, —C₃₋₈-cycloalkyl,—C₁₋₃-alkylene-phenyl, —C₁₋₃-alkylene-naphthyl, tetrahydropyranyl or—C(═O)—C₁₋₅-alkyl, using a suitable catalyst in an inert reaction mediumin the presence of hydrogen.

Preferably R represents methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl,—C(═O)—CH₃, —C(═O)—C₂H₅, —C(═O)—CH(CH₃)₂ or —C(═O)—C(CH₃)₃ in thecompound of general formula (II). Particularly preferably R representsmethyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl,phenethyl, tetrahydropyranyl or —C(═O)—CH₃ in the compound of generalformula (II).

More particularly preferably R represents methyl, benzyl ortetrahydropyranyl in the compound of general formula (II).

Even more particularly preferably R represents methyl in the compound ofgeneral formula (II). Thus,(2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol istransferred to (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amineby dehydration (step (b′)) and subsequent hydrogenation (step (b″)).

Preferably the hydrogenation in step (b″) is effected via homogeneouscatalysis in the presence of hydrogen after the dehydration step (b′).The hydrogen is preferably in gaseous form, although it is also possiblefor at least part of it to be dissolved in a liquid phase.

Preferably the homogeneous catalyst used for hydrogenation in step (b″)according to the present invention is a transition metal complex ofrhodium, iridium or ruthenium, particularly preferably a transitionmetal complex of rhodium or iridium, more particularly a transitionmetal complex of rhodium with diphosphine ligands.

Diphosphine ligands which can preferably be used are, for example knownfrom the following literature references: a) H. Brunner, W. Zettlmeier,Handbook of Enantioselective Catalysis. VCH Weinheim, 1993, vol. 2; b)R. Noyori et al. in Catalytic Asymmetric Synthesis Second Edition (I.Ojima, Ed.), Wiley-VCH, Weinheim, 2000; c) E. N. Jacobsen, A. Pfaltz, H.Yamamoto (Eds.), Comprehensive Asymmetric Catalysis Vol I-III, SpringerBerlin, 1999, and the references cited therein.

Particularly preferably the catalyst is chosen from the group consistingof rhodium (−)-DIPAMP[(R,R)-(+1,2-Bis[(2-methoxyphenyl)(phenyl)phosphino]ethane], rhodium(+)-DIPAMP[(S,S)-(+)-1,2-Bis[(2-methoxyphenyl)(phenyl)phosphino]ethane], rhodiumR-Solphos[R-(+)-N,N′-Dimethyl-7,7′-bis(diphenylphosphino)-3,3′,4,4′-tetrahydro-8,8′-bi-2H-1,4-benzoxazine]and rhodium S-Solphos[S-(−)-N,N′-Dimethyl-7,7′-bis(diphenylphosphino)-3,3′,4,4′-tetrahydro-8,8′-bi-2H-1,4-benzoxazine].The reaction parameters for the homogeneous hydrogenation in step (b″),such as, for example, pressure, temperature or reaction time, can varyover a wide range.

Preferably, the temperature during the homogeneous hydrogenation in step(b″) can be in each case from 0 to 250° C., particularly preferably from10 to 40° C. and very particularly preferably from 15 to 25° C.

The homogeneous hydrogenation in step (b″) can preferably be carried outat reduced pressure, at normal pressure or at elevated pressure,preferably in the range from 0.01 to 300 bar. It is particularlypreferred to carry out the reactions under pressure in a range from 3 to20 bar, in particular from 8 to 12 bar.

The reaction time can vary in dependence on various parameters, such as,for example, temperature, pressure, nature of the compound to be reactedor the properties of the catalyst, and can be determined for the processin question by the person skilled in the art using preliminary tests.

The dehydration step (b′) is preferably acid-catalysed. Preferably theacid is selected from the group consisting of formic acid, hydrochloricacid, acetic acid, sulfuric acid, hydrobromic acid, methanesulfonic acidor any mixture thereof. It is preferable if the acid is employed in ahigh concentration. Particularly preferably the concentration of thehydrochloric acid is >20%, preferably >30%, particularly preferably >35%by weight. Alternatively, the acid can also be used in gaseous form.

The compounds of general formula II and VII used in step (b′) accordingto the present invention are preferably in liquid phase and to that endare preferably mixed with or dissolved in a reaction medium that isliquid under the particular reaction conditions.

Examples of suitable reaction media are water, acetic acid, formic acid,toluene, hydrochloric acid, sulfuric acid, hydrobromic acid,methanesulfonic acid or any mixture thereof. Of course, it is alsopossible to use mixtures or multiphase systems comprising two or more ofthe above-mentioned liquids in the processes according to the presentinvention. A reaction in supercritical CO₂ as solvent is also possible.

The reaction parameters for the dehydration in step (b′), such as, forexample, pressure, temperature or reaction time, can vary over a widerange.

It is preferable if the reaction temperature in step (b′) is between 35and 100° C., particularly preferably 45 and 80° C., more particularlypreferably between 50 and 60° C.

The dehydration step (b′) can preferably be carried out at reducedpressure, at normal pressure or at elevated pressure, preferably in therange from 0.01 to 300 bar. It is particularly preferred to carry outthe reactions under pressure in a range from 0.5 to 5 bar, in particularfrom 0.5 to 1.5 bar.

The reaction time can vary in dependence on various parameters, such as,for example, temperature, pressure, nature of the compound to be reactedor the properties of the catalyst, and can be determined for the processin question by the person skilled in the art using preliminary tests. Itis preferable if the reaction time of step (b′) is between 2 and 10 h,particularly preferably between 3 and 8 h, more particularly preferablybetween 4 and 6 h.

The continuous removal of samples in order to monitor the reaction, forexample by means of gas chromatography methods, is also possible,optionally in combination with regulation of the corresponding processparameters.

The concentration of the acid in the reaction medium is preferably 20 to26 M in case of formic acid, 5 to 18 M in case of acetic acid, 8 to 14 Min case of hydrochloric acid and 4 to 36 M, more preferably 4 to 18 M,in case of sulfuric acid.

The particular compound of general formula (VII) obtained can beisolated and/or purified by conventional methods known to the personskilled in the art.

Alternatively, the dehydration step (b′) can also be carried out in thepresence of at least one acidic catalyst, which can preferably beselected from the group consisting of ion-exchange resins, zeolites,heteropoly acids, phosphates, sulfates and optionally mixed metaloxides.

The term catalyst within the context of the present invention includesboth catalytically active materials themselves and inert materials thatare provided with a catalytically active material. Accordingly, thecatalytically active material can, for example, be applied to an inertcarrier or can be present in a mixture with an inert material. Therecome into consideration as inert carrier or inert material, for example,carbon and other materials known to the person skilled in the art.

Suitable catalysts and their preparation are known per se to the personskilled in the art, for example from Venuto, P. B., Microporous Mater.,1994, 2, 297; Hölderich, W. F., van Bekkum, H., Stud. Surf. Sci. Catal.,1991, 58, 631, Hölderich, W. F., Proceedings of the 10th InternationalCongress on Catalysis, 1992, Budapest, Guczi, L. et al. (editors), “NewFrontiers in Catalysis”, 1993, Elsevier Science Publishers, Kozhenikov,I. V., Catal. Rev. Sci. Eng., 1995, 37, 311, Song, X., Sayari, A.,Catal. Rev. Sci. Eng., 1996, 38, 329. The corresponding literaturedescriptions are incorporated herein by reference and form part of thedisclosure.

They are suitable for the dehydration in particular those ion-exchangeresins that carry sulfonic acid groups are used.

Preference is given to ion-exchange resins based ontetrafluoroethylene/perfluorovinyl ether copolymers, optionally in theform of their silica nanocomposites, as are described, for example, inthe literature publications of Olah et al. Synthesis, 1996, 513-531 andHarmer et al. Green Chemistry, 2000, 7-14, the correspondingdescriptions of which are incorporated herein by reference and form partof the disclosure. Corresponding products are available commercially,for example under the name Nafion®, and can also be used in that form inthe processes according to the present invention.

Preference is further given to ion-exchange resins based onstyrene/divinylbenzene copolymers, which can be prepared by conventionalprocesses known to the person skilled in the art.

There come into consideration for the dehydration particularlypreferably sulfonic-acid-group-carrying ion-exchange resins based onstyrene/divinylbenzene copolymers, as are marketed, for example, underthe name Amberlyst® by Rohm & Haas and which can also be used as such inthe processes according to the present invention. These ion-exchangeresins are distinguished in particular by their stability towards waterand alcohols, even at elevated temperatures, for example from 130 to160° C.

The degree of crosslinking and the structure of these ion-exchangeresins can vary. For example, mention may be made of macroporousion-exchange resins having heterogeneous pore diameter distribution,isoporous ion-exchange resins having virtually uniform pore diameterdistribution, or gel-like ion-exchange resins having no or virtually nopores. The macroporous resins in particular can be used with particularadvantage for heterogeneous catalysis in the liquid phase.

Particularly suitable macroporous resins having a mean pore diameter offrom 20 to 30 nm and a minimum concentration of active groups of from4.70 to 5.45 equivalents per kg of resin are available commerciallyunder the names Amberlyst® 15, Amberlyst® 35 and Amberlyst® 36 andaccordingly can also be used in the processes according to the presentinvention.

It is likewise preferred to carry out the dehydration in the presence ofan acidic catalyst based on metal oxides such as, for example, SiO₂,Al₂O₃, TiO₂, Nb₂O₅, B₂O₃ or based on mixed metal oxides such as, forexample, Al₂O₃/SiO₂ or Al₂O₃/B₂O₃.

Preferably, the temperature for dehydration (b′) when using an acidiccatalyst as describe above is in each case from 20 to 250° C.,particularly preferably from 50 to 180° C. and very particularlypreferably from 100 to 160° C.

The ratio of acidic catalyst and compound of general formula (II) ispreferably in the range from 1:200 to 1:1, in particular from 1:4 to1:2.

After the dehydration, the catalyst can be separated from the reactionmixture in a simple manner, preferably by filtration. The particularcompound of general formula (VII) obtained be isolated and/or purifiedby conventional methods known to the person skilled in the art.

Alternatively, the dehydration step (b′) can also be carried out bysubjecting a compound of general formula (II) to an excess of thionylchloride, optionally in a reaction medium, preferably in a reactionmedium selected from the group consisting of diethylether,tetrahydrofuran, toluene, 2-methyltetrahydrofuran, dioxane,tert-butyl-methylether and mixtures thereof, and subsequent heating ofthe thus obtained reaction mixture to 40° C. to 120° C., preferably to80° C. to 120° C.

The hydrogenation of step (b″) can also be effected via heterogeneouscatalysis with hydrogen. The hydrogen is preferably in gaseous form,although it is also possible for at least part of it to be dissolved ina liquid phase.

Heterogeneous catalysis within the context of the present inventionmeans that the catalysts used in step (b″) are in each case present inthe solid state of aggregation.

Preferably the heterogeneous catalyst used for hydrogenation in step(b″) according to the present invention contains one or more transitionmetals, these metals can preferably be selected from the groupconsisting of Cu, Ag, Au, Zn, Cd, Hg, V, Nb, Ta, Cr, Mo, W, Fe, Ru, Os,Co, Rh, Ir, Ni, Pd, Pt, particularly preferably from the groupconsisting of Ru, Rh, Pd, Pt and Ni.

The corresponding catalysts can preferably contain one or more of theabove-mentioned transition metals in the same or different oxidationstates. It may also be preferable for the corresponding catalysts tocontain one or more of the above-mentioned transition metals in two ormore different oxidation states.

The preparation of catalysts doped with transition metals can be carriedout by conventional processes known to the person skilled in the art.

Preferably the catalyst used for hydrogenation in step (b″) is selectedfrom the group consisting of Raney nickel, palladium, palladium oncarbon (1-10 wt. %, preferably 5 wt. %), platinum, platinum on carbon(1-10 wt. %, preferably 5 wt. %), ruthenium on carbon (1-10 wt. %,preferably 5 wt. %) and rhodium on carbon (1-10 wt. %, preferably 5 wt.%), more preferably palladium on carbon (1-10 wt. %, preferably 5 wt. %)is used as the catalyst for hydrogenation in step (b″).

The compounds of general formula VII or III used in step (b″) accordingto the present invention are preferably in liquid phase and to that endare preferably mixed with or dissolved in a reaction medium that isliquid under the particular reaction conditions.

Examples of suitable reaction media are methanol, ethanol, isopropanol,n-butanol, n-propanol, toluene, heptane, hexane, pentane, acetic acid,ethyl acetate, formic acid, hydrochloric acid, hydrobromic acid,sulfuric acid and mixtures thereof. More preferably ethanol is used asthe reaction medium in step (b″). Of course, it is also possible to usemixtures or multiphase systems comprising two or more of theabove-mentioned liquids in the processes according to the presentinvention. A reaction in supercritical CO₂ as solvent is also possible.

The reaction parameters for the heterogeneous hydrogenation in step(b″), such as, for example, pressure, temperature or reaction time, canvary over a wide range both.

Preferably, the temperature during the heterogeneous hydrogenation instep (b″) is in each case from 0 to 250° C., particularly preferablyfrom 15 to 180° C. and very particularly preferably from 15 to 30° C.

The heterogeneous hydrogenation in step (b″) can preferably be carriedout at reduced pressure, at normal pressure or at elevated pressure,preferably in the range from 1 to 300 bar. It is particularly preferredto carry out the reactions under pressure in a range from 2 to 10 bar,in particular from 4 to 10 bar.

The reaction time can vary in dependence on various parameters, such as,for example, temperature, pressure, nature of the compound to be reactedor the properties of the catalyst, and can be determined for the processin question by the person skilled in the art using preliminary tests.

The continuous removal of samples in order to monitor the reaction, forexample by means of gas chromatography methods, is also possible,optionally in combination with regulation of the corresponding processparameters.

The total amount of the catalyst(s) used depends on various factors,such as, for example, the ratio of the catalytically active component toany inert material present, or the nature of the surface of thecatalyst(s). The optimal amount of catalyst(s) for a particular reactioncan be determined by the person skilled in the art using preliminarytests.

The particular compound of general formula (III) obtained can beisolated and/or purified by conventional methods known to the personskilled in the art.

In another embodiment of the invention step b) (scheme 1) is a directreplacement reaction of the OH group by H, preferably carried out in aone-pot reaction. More preferably an OH is replaced by H.

The steps according to the present invention can each be carried outdiscontinuously (batchwise) or continuously, preference being given tothe discontinuous procedure.

There come into consideration as the reactor for the discontinuousprocedure, for example, a slurry reactor, and for the continuousprocedure a fixed-bed reactor or loop reactor.

In the following a process for the preparation of(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochlorideis described.

EXAMPLE Preparation of(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol Hydrochloride

Step (a′): Preparation of 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (VIa)

1-(3-Methoxyphenyl)propan-1-one (16.42 kg, 100 mol), dimethylaminehydrochloride (8.97 kg, 110 mol), paraformaldehyde (3.30 kg, 110 mol)and aqueous hydrochloric acid (32% by weight, 1.14 kg) were dissolved inethanol under a nitrogen atmosphere in a 100 L (L=liter) double jacketvessel equipped with an electrical impeller stirrer, a gas transitionline, Pt100 temperature measuring equipment and an oil basedcooling/heating system. The reaction mixture was refluxed for 16 hours,cooled to 25° C. within 3.5 hours and stirred for 1 hour at thattemperature. The suspension was separated via a centrifuge and washedthree times with 7 L acetone each.3-(Dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one hydrochloridewas dissolved in water (12.5 L) and tert-butyl-methyl-ether (8.5 L) andstirred at room temperature.

Aqueous sodium hydroxide solution (32% by weight) was added until a pHvalue between 10.0 and 10.5 was reached and the phases were allowed toseparate. The organic phase was distilled off under reduced pressureuntil at a temperature of 40° C. a pressure of 5 mbar was reached.3-(Dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one was obtainedas a pale yellow oil (20.75 kg, 94%) that was used in the next stepwithout further purification.

Step (a″): Preparation of(S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (Ia) 1.a. Preparation of(S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one(2R,3R)—O,O′-dibenzoyltartrate in Acetone

(2R,3R)—O,O′-Dibenzoyl tartaric acid monohydrate (189.1 g, 0.5 mol) wasdissolved in acetone (550 mL) in a 2 L reaction plant equipped with amechanical stirrer, temperature measuring equipment and an oil bath and3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (110.6 g, 0.5mol) was added. The reaction mixture was heated to 35° C. to 40° C. for27 hours and allowed to cool to 25° C. The suspension was siphoned offand (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one(2R,3R)—O,O′-dibenzoyltartrate was obtained as a colorless solid (233.2g, 80.5%, ee 96.9%, ee=enantiomeric excess).

1. b. Preparation of(S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one(2R,3R)—O,O′-dibenzoyltartrate in Acetone/Methanol

(2R,3R)—O,O′-Dibenzoyl tartaric acid monohydrate (2.1 kg, 5.5 mol) wasdissolved in a mixture of methanol (555 mL) and acetone (3340 mL) in a10 L double jacket vessel equipped with an electrical impeller stirrer,a gas transition line, Pt100 temperature measuring equipment and an oilbased cooling/heating system and3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (1.23 kg,5.56 mol) was added. The reaction mixture was heated to 35° C. to 40° C.for 24 hours and allowed to cool to 25° C. The suspension was siphonedoff and (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one(2R,3R)—O,O′-dibenzoyltartrate was obtained as a colorless solid (2.38kg, 74%, ee 98.4%).

2. Preparation of(S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (Ia)

(S)-3-(Dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one(2R,3R)—O,O′-dibenzoyltartrate (968 g, 1.67 mmol, ee 98%) was suspendedin tert-butylmethyl ether (6 L) in a 10 L double jacket vessel equippedwith an electrical impeller stirrer, a gas transition line, Pt100temperature measuring equipment and an oil based cooling/heating systemand diethylamine (384 g, 5.25 mol) was added. The reaction mixture wasstirred at 20° C. to 25° C. for 90 minutes and a solid was siphoned off.The filtrate was concentrated at a temperature of 40° C. in vacuo untila pressure of 4 mbar was reached.(S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one wasobtained as a colorless oil (356.7 g, 96.5%, ee 98%).

Step (a): Preparation of(2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol (IIa)

1. Magnesium turnings (93.57 g, 3.85 mol) were suspended in dry ethylether (2 L) in a 10 L double jacket vessel equipped with an electricalimpeller stirrer, a gas transition line, Pt100 temperature measuringequipment and an oil based cooling/heating system and ethyl bromide (25g, 0.23 mol) was added. After the reaction has started further ethylbromide (438.6 g, 4.02 mol) was added within 90 minutes below atemperature of 35° C. and the reaction mixture was stirred for anotherhour. The reaction mixture was cooled to 10° C. to 15° C.,(S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (774.6 g,3.5 mol, ee 98%) dissolved in diethyl ether (0.8 L) was added and thereaction mixture was stirred for another two hours. The reaction mixturewas cooled to 5° C. and aqueous ammonium hydrogensulfate solution (10%by weight, 2 L) was added. The phases were separated and the organicphase was concentrated in vacuo at 40° C. until a pressure of 5 mbar wasreached.(2S,3R)-1-(Dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol (862.3g, 98%) was obtained as a colorless oil (ee 98%).

2. (S)-3-(Dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (774.6g, 3.5 mol, ee 95%) was dissolved in dry tetrahydrofuran (800 mL) in a10 L double jacket vessel equipped with an electrical impeller stirrer,a gas transition line, Pt100 temperature measuring equipment and an oilbased cooling/heating system and ethyl magnesium bromide (2 L, 2 M inTHF) was added at a temperature of 15° C. within 2 hours. The reactionmixture was stirred for two hours at that temperature, cooled to 5° C.and aqueous ammonium hydrogen sulfate solution (10% by weight, 2 L) wasadded. The phases were separated and the organic phase was concentratedin vacuo at 40° C. until a pressure of 5 mbar was reached.(2S,3R)-1-(Dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol (871.1g, 99%) was obtained as a colorless oil (ee 95%).

Step (b′): Preparation of(R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine (VIIa)

1. (2S,3R)-1-(Dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol(754.1 g, 3 mol, ee 95%) were dissolved in acetone (5 L) in a 10 Ldouble jacket vessel equipped with an electrical impeller stirrer, a gastransition line, Pt100 temperature measuring equipment and an oil basedcooling/heating system. Hydrogen chloride (110 g, 3.0 mol) wastransferred within 15 minutes at a temperature of 15° C. through thereaction mixture. The reaction mixture was cooled to 0° C. to 5° C. andafter 24 hours at that temperature siphoned off. The product was storedat 40° C. and 10 mbar for 14 hours in a drying oven.(2S,3R)-1-(Dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-olhydrochloride was obtained as a colorless solid (722.3 g, 83.7%, ee100%).

2. (2S,3R)-1-(Dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-olhydrochloride obtained as described above was put into a 250 mL threenecked flask equipped with a thermometer, a mechanical compressed airstirrer, reflux condenser and oil bath and aqueous hydrogen chloridesolution (150 mL, 36% by weight) was added. The reaction mixture washeated to 55° C. for 5 hours and allowed to cool to 20° C. Aqueoussodium hydroxide solution (33% by weight) was added while cooling untila pH value of 11 was reached. Ethyl acetate (150 mL) was added, thereaction mixture was stirred for 10 minutes, the phases were separatedand ethyl acetate was removed in vacuo at 60° C. until a pressure of 10mbar was reached.(R)-3-(3-Methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine (21 g, 90%) wasobtained as an oily residue (Z/E ratio 4.5:1).

Step (b″): Preparation of(2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine Hydrochloride(IIIa)

1. (R)-3-(3-Methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine (5 kg, 21.43mmol) was dissolved in dry ethanol (13 L) at a temperature of 25° C. androtational stirring frequency of 850±150 per minute in a double jackethydrogenation apparatus equipped with a stationary mounted lid having ahydrogen and nitrogen supply, electric gassing stirrer, Pt100temperature measuring equipment, inspecting glass and gas controller“Büchi bpc”. The hydrogenation apparatus was flooded with nitrogen.Palladium on charcoal (375 g, 5% by weight) was suspended in aqueoushydrogen chloride (675 g, 32% by weight) and added to the reactionmixture. The hydrogenation apparatus was flooded again with nitrogen andthe reaction was carried out at a primary pressure of hydrogen of 5 barand an internal hydrogen pressure of 1 bar until the reaction wascomplete. The hydrogenation apparatus was flooded with nitrogen and thecatalyst was filtered off on a one layered filter with filtering earth.The filtrate was concentrated in vacuo. The residue was take up in ethylacetate and aqueous sodium hydroxide (10% by weight, 3.7 L) was added at20° C. until a pH value of 10 to 12 was reached. The organic phase wasconcentrated in vacuo at 45° C. to 50° C. until a pressure of 5 mbar wasreached. The oily residue was a mixture of(2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine and(2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine (4.5 kg, 95%,ratio 5.5 (R,R):1 (R,S)).

2. A mixture of(2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine and(2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine (10 kg, 42.56mol, ratio 5.5:1) was dissolved in acetone (50 L) in a 100 L doublejacket vessel equipped with an electrical impeller stirrer, a gastransition line, Pt100 temperature measuring equipment and an oil basedcooling/heating system. Hydrogen chloride (1.55 kg, 42.51 mol) wastransferred within 15 minutes at a temperature of 5° C. to 25° C.through the reaction mixture. The reaction mixture was cooled to 0° C.to 5° C. and centrifuged after 2 hours of stirring. The humid solid wasput into a stirring vessel, acetone (30 L) was added and the reactionmixture was heated to reflux for 15 minutes. After cooling to 15° C. to20° C. the product was centrifuged and stored at 40° C. to 50° C. and150 mbar for 14 hours in a drying oven.(2R,3R)-3-(3-Methoxyphenyl)-N,N,2-trimethylpentan-1-amine hydrochloride(7.17 kg, 63%) was obtained as a colorless solid with a diastereomericexcess of 100%).

Step (c): Preparation of(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol Hydrochloride(IV)

1. (2R,3R)-3-(3-Methoxyphenyl)-N,N,2-trimethylpentan-1-aminehydrochloride (5 kg, 18.4 mol) was dissolved in methane sulfonic acid(19.5 L) in a 100 L double jacket vessel equipped with an electricalimpeller stirrer, a gas transition line, Pt100 temperature measuringequipment and an oil based cooling/heating system and methionine (3.35kg, 22.5 mol) was added. The reaction mixture was stirred at atemperature of 75° C. to 80° C. for 16 hours, cooled to 15° C. to 25° C.and water (12.5 L) was slowly added at that temperature. Aqueous sodiumhydroxide solution (ca. 28 L, 32% by weight) was added until a pH valueof 10 to 12 was reached while the temperature was kept below 50° C.Ethyl acetate (15 L) was added and the reaction mixture was stirred for15 minutes at a rotational stirring frequency of 150 per minute. Thephases were separated and the organic phase was washed with water (15L). Activated charcoal (0.05 kg) was added to the organic phase andfiltered off after 30 minutes of stirring. The solvent was removed invacuo at a temperature of 40° C. to 50° C. until a pressure of 50 mbarwas reached. The residue was used in the next step without furtherpurification.

2. The residue obtained as described above was dissolved in acetone (25L) while stirring and hydrogen chloride (0.78 kg, 21.4 mol) wastransferred through the reaction mixture at a temperature of 20° C. to25° C. The suspension was stirred for 3 hours at a temperature of 0° C.to 5° C. and centrifuged. Isopropanol (35 L) was added to the humidsolid in a reaction vessel and the reaction mixture was heated to refluxfor 15 minutes. The reaction mixture was cooled to 0° C. to 5° C. andstirred for 3 hours at that temperature. After centrifugation theproduct was stored at 30° C. to 40° C. and 150 mbar for 16 hours in adrying oven. (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenolhydrochloride (4.18 kg, 88%) were obtained as a colorless solid with apurity of 100%.

1. A process for preparing(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acidaddition salt thereof, comprising the step of (a) reacting a compound ofgeneral formula (I),

wherein R represents —C₁₋₆-alkyl, —C₃₋₈-cycloalkyl,—C₁₋₃-alkylene-phenyl, —C₁₋₃-alkylene-naphthyl, tetrahydropyranyl or—C(═O)—C₁₋₆-alkyl, with ethyl magnesium halide in an inert reactionmedium under Grignard conditions, (b) transferring the thus obtainedcompound of general formula (II),

wherein R has the above defined meaning, to a compound of generalformula (III),

wherein R has the above defined meaning, optionally in form of an acidaddition salt, (c) deprotecting the thus obtained compound of generalformula (III) to obtain(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula(IV),

(d) optionally converting the thus obtained(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol into an acidaddition salt.
 2. A process according to claim 1, characterized in thatR represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, —C(═O)—CH₃,—C(═O)—C₂H₅, —C(═O)—CH(CH₃)₂ or —C(═O)—C(CH₃)₃.
 3. A process accordingto claim 1 or 2, characterized in that R represents methyl, ethyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl,tetrahydropyranyl or —C(═O)—CH₃.
 4. A process according to any of claims1 to 3, characterized in that R represents methyl, benzyl ortetrahydropyranyl.
 5. A process according to any of claims 1 to 4,characterized in that the ethyl magnesium halide used in step (a) is thechloride or bromide.
 6. A process according to any one of claims 1 to 5,characterized in that the inert reaction medium is selected from thegroup consisting of diethyl ether, tetrahydrofuran,2-methyltetrahydrofuran, tert-butyl-methylether, diisopropylether or anymixture thereof.
 7. A process according to any one of claims 1 to 6,characterized in that a compound of general formula (I) was obtained by(a′) reacting a compound of general formula (V),

wherein R represents —C₁₋₆-alkyl, —C₃₋₈-cycloalkyl,—C₁₋₃-alkylene-phenyl, —C₁₋₃-alkylene-naphthyl, tetrahydropyranyl or—C(═O)—C₁₋₆-alkyl, with dimethylamine hydrochloride and paraformaldehydein an inert reaction medium under Mannich conditions and (a″) subsequentresolution of the thus obtained compound of general formula (VI),

wherein R has the above defined meaning.
 8. A process according to claim7, characterized in that R represents methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl,tetrahydropyranyl, —C(═O)—CH₃, —C(═O)—C₂H₅, —C(═O)—CH(CH₃)₂ or—C(═O)—C(CH₃)₃.
 9. A process according to claim 7 or 8, characterized inthat R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or —C(═O)—CH₃.
 10. Aprocess according to any of claims 7 to 9, characterized in that Rrepresents methyl, benzyl or tetrahydropyranyl.
 11. A process accordingto any of claims 7 to 10, characterized in that the resolution in step(a″) is performed by reacting a compound of general formula (VI) with achiral acid selected from the group consisting of L-(−)-dibenzoyltartaric acid, L-(−)-dibenzoyl tartaric acid.H₂O and D-(−)-tartaricacid, subsequent separation of the thus obtained salt and liberation ofthe corresponding compound of general formula (I) in form of the freebase.
 12. A process according to claim 11, characterized in that theresolution is performed in an alcoholic reaction medium selected fromthe group consisting of methanol, ethanol, 1-propanol, 2-propanol andany mixture thereof.
 13. A process according to any of claims 1 to 12,characterized in that the transfer according to step (b) is performed by(b′) subjecting the compound of general formula (II) to dehydration and(b″) hydrogenation of the thus obtained compound of general formula(VII),

wherein R represents —C₁₋₆-alkyl, —C₃₋₈-cycloalkyl,—C₁₋₃-alkylene-phenyl, —C₁₋₃-alkylene-naphthyl, tetrahydropyranyl or—C(═O)—C₁₋₆-alkyl, using a suitable catalyst in an inert reaction mediumin the presence of hydrogen.
 14. A process according to claim 13,characterized in that R represents methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl,tetrahydropyranyl, —C(═O)—CH₃, —C(═O)—C₂H₅, —C(═O)—CH(CH₃)₂ or—C(═O)—C(CH₃)₃.
 15. A process according to claim 13 or 14, characterizedin that R represents methyl, ethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or—C(═O)—CH₃.
 16. A process according to any of claims 13 to 15,characterized in that R represents methyl, benzyl or tetrahydropyranyl.17. A process according to any of claims 13 to 16, characterized in thatafter the dehydration step (b′) the hydrogenation in step (b″) iseffected via homogeneous catalysis.
 18. A process according to any ofclaims 13 to 17, characterized in that the dehydration step (b′) isacid-catalysed.
 19. A process according to claim 18, characterized inthat the acid is selected from the group consisting of formic acid,hydrochloric acid, sulfuric acid, methanesulfonic acid, hydrobromic acidor any mixture thereof.
 20. A process according to any of claims 13 to16, characterized in that the hydrogenation of step (b″) is effected viaheterogeneous catalysis.
 21. A process according to claim 20,characterized in that the catalyst used for hydrogenation is selectedfrom the group consisting of Raney nickel, palladium, palladium oncarbon, platinum, platinum on carbon, ruthenium on carbon or rhodium oncarbon.
 22. A process according to any of claims 13 to 21, characterizedin that the reaction medium is selected from the group consisting ofdiethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,tert-butyl-methylether, diisopropylether or any mixtures thereof.
 23. Aprocess according to any of claims 1 to 12 characterized in that step b)is a direct replacement reaction of the OH group by H, preferablycarried out in a one-pot reaction.